MUC5AC 프로모터의 유전자 다형성과 천식과의 연관성

한선숙 ( Seon Sook Han ),성지현 ( Ji Hyun Sung ),이미은 ( Mi Eun Lee ),이승준 ( Seung Joon Lee ),이성준 ( Sung Joon Lee ),김우진 ( Woo Jin Kim ) 대한결핵 및 호흡기학회 2007 Tuberculosis and Respiratory Diseases Vol.63 No.3

연구배경: 기관지 점액의 과분비는 천식의 중요한 기전중의 하나이며, 특히천식 환자에서는 MUC5AC가 중요한 역할을 하는 것으로 알려져 있다. MUC5AC는 다양한 유전자 다형성을 갖는 것으로 알려져 있으나 MUC5AC 유전자 다형성과 천식과의 관계를 본 연구는 거의 없는 실정이다. 따라서 본 연구는 MUC5AC 프로모터 부위의 유전자 다형성과 천식과의 관계를 조사하였다. 방법: 강원대학교 병원에서 78명의 천식환자와 이들과 성별, 나이가 일치하는 78명의 대조군을 선정하였다. 이들로부터 전혈을 채취하여 DNA를 분리하여 PCR과 RFLP를 이용하여 MUC5AC 프로모터의 -1274G>A 유전자 다형성을 분석하였다. 모든 대상환자는 의무기록지를 검토하여 주된 증상과 투여 약제를 확인하였으며, 이들에서의 폐기능, 총 호산구수, 혈청 IgE, 피부반응검사 결과를 조사하였다. 결과: 천식환자의 평균 나이는 47.7±16.1세, 남자가 38.5%이었으며, 평균 FEV1은 84.4±22.3%이었다. MUC5AC 프로모터의 -1274G>A 유전자 다형성은 두 군간에 차이가 없었다(p=0.752, Cod). 천식 증상의 심한 정도, FEV1, 총 호산구수, 혈청 IgE, PC20, 아토피의 유무에 따라서도 MUC5AC 프로모터의 -1274G>A 유전자 다형성은 차이가 없었다. 결론: MUC5AC 프로모터의 -1274G>A 유전자 다형성은 천식과는 무관하였으며, 여러 가지 임상적인 지표들과도 상관관계를 보이지 않았다. Background: Airway mucus hypersecretion plays an important role in the pathogenesis of asthma, and is associated with the induction of MUC5AC expression in airway secretion. The MUC5AC gene is highly polymorphic; however, there are few studies about the association between the polymorphisms of the MUC5AC gene and asthma susceptibility or asthma phenotypes. We have investigated the association of MUC5AC promoter polymorphisms with the risk of asthma and asthma phenotypes. Methods: We determined the genotypes of the MUC5AC promoter (-1274G>A) in 78 asthma patients and in 78 age, sex-matched control individuals in the Korean population. Genomic DNAs from blood were analyzed by PCR and RFLP (restriction fragment length polymorphism) determination. We examined FEV1, total eosinophil count, serum IgE level, PC20 and the presence of atopy (by a skin test) in asthma patients. Results: The mean age of the patients was 47.7 ± 16.1 years and 38.5% were men, and the mean FEV1 was 84.4 ± 22.3% of predicted in the asthma patients. The -1274G>A polymorphism of the MUC5AC promoter in asthma patients was not significantly different as compared with normal individuals (GG 57.7%, AG 34.6% and AA 7.7% in asthma patients vs. GG 56.4%, AG 38.5% and AA 5.1% in control subject, p = 0.752, Cod). Several clinical parameters in asthma patients such as FEV1, total eosinophil count, serum IgE level, PC20 and the presence of atopy, were not associated with the -1274G>A polymorphism of the MUC5AC promoter. Conclusion: The -1274G>A single nucleotide polymorphism (SNP) frequency of the MUC5AC promoter was not associated with asthma in a Korean population. (Tuberc Respir Dis 2007; 63: 235-241)

담석 성분에 따른 담낭점막의 MUC3, MUC5AC, MUC6 및 Epidermal Growth Factor Receptor 발현

김효정 ( Kim Hyo Jeong ),김재선 ( Kim Jae Seon ),김경오 ( Kim Gyeong O ),박기호 ( Park Gi Ho ),임형준 ( Im Hyeong Jun ),김진용 ( Kim Jin Yong ),연종은 ( Yeon Jong Eun ),박종재 ( Park Jong Jae ),심재정 ( Sim Jae Jeong ),변관수 ( By 대한소화기학회 2003 대한소화기학회지 Vol.42 No.4

인체 호흡기 상피세포에서 담배특이니트로사민에 의한 점액유전자 발현 및 기전

곽소영,최윤석,나형균,배창훈,송시연,김용대 대한비과학회 2020 Journal of rhinology Vol.27 No.1

Background and Objectives: Nicotine is oxidized into tobacco-specific nitrosamines (TSNAs; NAB, NAT, NNN, NNAL, NNK) at high temperature and high pressure. TSNAs are associated with airway diseases characterized by mucus hypersecretion as a major pathophysiologic phenomenon. The aim of study is to investigate the effect of TSNAs on mucin overexpression and its molecular mechanism in human airway epithelial cells. Materials and Method: The cytotoxicity of TSNAs was evaluated using EX-Cytox and inverted microscopy. The mRNA and protein levels of MUC5AC and MUC5B were measured using real-time PCR and ELISA. Results: NAB, NNN, NNAL, and NNK did not affect cell viability. NAT did not affect cell viability up to a concentration of 100 μM in human airway epithelial cells. NAT, NNN, NNAL, and NNK significantly induced MUC5AC expression, but not MUC5B expression. NAB did not affect the expression of MUC5AC and MUC5B. Propranolol (a β-adrenergic receptor antagonist) inhibited NAT, NNN, NNAL, and NNK-induced MUC5AC expression, whereas α-bungarotoxin (an α7-nicotinic acetylcholine receptor antagonist) only inhibited NNN- and NNK-induced MUC5AC expression. Conclusion: These results suggested that NAT, NNN, NNAL, and NNK induce MUC5AC expression through β-adrenergic receptor and/or α7-nicotinic acetylcholine receptor in human airway epithelial cells, which may be involved in mucus hypersecretion in inflammatory airway diseases. Background and Objectives: Nicotine is oxidized into tobacco-specific nitrosamines (TSNAs; NAB, NAT, NNN, NNAL, NNK) at high temperature and high pressure. TSNAs are associated with airway diseases characterized by mucus hypersecretion as a major pathophysiologic phenomenon. The aim of study is to investigate the effect of TSNAs on mucin overexpression and its molecular mechanism in human airway epithelial cells.Materials and Method: The cytotoxicity of TSNAs was evaluated using EX-Cytox and inverted microscopy. The mRNA and protein levels of MUC5AC and MUC5B were measured using real-time PCR and ELISA.Results: NAB, NNN, NNAL, and NNK did not affect cell viability. NAT did not affect cell viability up to a concentration of 100 μM in human airway epithelial cells. NAT, NNN, NNAL, and NNK significantly induced MUC5AC expression, but not MUC5B expression. NAB did not affect the expression of MUC5AC and MUC5B. Propranolol (a β-adrenergic receptor antagonist) inhibited NAT, NNN, NNAL, and NNK-induced MUC5AC expression, whereas α-bungarotoxin (an α7-nicotinic acetylcholine receptor antagonist) only inhibited NNN- and NNK-induced MUC5AC expression.Conclusion: These results suggested that NAT, NNN, NNAL, and NNK induce MUC5AC expression through β-adrenergic receptor and/or α7-nicotinic acetylcholine receptor in human airway epithelial cells, which may be involved in mucus hypersecretion in inflammatory airway diseases.

사람 코점막 배세포에서 MUC5AC mRNA의 발현 양상

강성석,김창훈,김현웅,이정권,윤주헌 대한이비인후과학회 2001 대한이비인후과학회지 두경부외과학 Vol.44 No.4

Helicobacter pylori 제균치료 후의 위전정부 뮤신 발현의 변화

마명신,황진수,나성일,이길홍,최정기,이승옥,강명재,김대곤,안득수,이수택 대한내과학회 2003 대한내과학회지 Vol.65 No.1

Background : Helicobacter pylori colonizes the gastric surface epithelium and the mucus gel layer. It has been known that H. pylori infection decreased the gastric mucin expression. The aim of this study was to determine the effect of H. pylori eradication on mucin expression (MUC5AC, MUC6 and MUC1) in the gastric epithelium. Methods : This study included 20 patients positive for H. pylori whom successful eradication was performed between March 1998 and December 1999. H. pylori status was determined by histology, rapid urase test and urea breath test. Gastric antral biopsy specimens were examined by immunohistochemistry for mucin (MUC5AC, MUC6 and MUC1) expression. The distribution of epithelial cells expressing MUC5AC was calculated at two sites (surface mucous cells, pyloric glands). Two scores system (weak-strong) was used to assess staining intensity. Results : There was a gradient of MUC5AC expression, higher to lower from the surface to the glands. Increased MUC5AC expression in the surface mucous cell (p=0.013) and in the glands (p=0.008) was found after H. pylori eradication. MUC6 and MUC1 distribution was not changed after H. pylori eradication. Conclusion : MUC5AC expression was increased after H. pylori eradication. These results suggest that MUC5AC may relate in the pathogenesis of H. pylori.(Korean J Med 64:21-27, 2003) 목적 : 만성 위염과 소화성궤양, 위암 그리고 말트림 프종의 발생과 관련이 있는 H. pylori는 위점막표면에 기생하면서 점액의 주요성분인 뮤신에 변화를 일으킨다 고 알려져 있다. 본 연구는 성공적으로 제균치료가 되었 던 H. pylori에 감염된 환자들을 대상으로 위의 표재성 세포 중 표재성 점액세포와 유문선 세포에서 각각 뮤신 분비에 어떤 변화가 일어나는지 알아보고자 하였다. 대상 및 방법 : 1998년 3월부터 1999년 12월까지 전 북대학교 병원 소화기내과에서 상복부 불편감으로 내원 한 환자를 대상으로 하였다. 역류성 식도염이 있거나 위 내시경상 장상피화생이 있는 환자는 환자군에서 제외되 었다. 위 생검 조직검사에서 H. pylori 양성을 보였고, rapid urase test (CLO test)를 실시하거나 urea breath test를 실시하여 H. pylori 양성을 보인 환자 중 amoxacillin 2 g/d, omeprazole 40 mg/d, clarithromycin 1 g/d 을 일주일간 투여하여 성공적으로 제균치료가 되었던 환자 20명을 대상으로 하였다. 이들은 제균치료가 끝난 뒤 최소 1개월 후에 다시 위내시경을 실시했으며 rapid urase test (CLO test)를 실시하거나 urea breath test를 실시하여 H. pylori 제균을 확인하였다. 이들 제균치료 가 성공적이었던 20명의 환자들을 대상으로 후향적인 분석을 시행하였다. 남자는 9명이었고, 여자는 11명이었 으며 중앙 연령은 42세(32∼65세)였다. 위궤양이 4명, 십 이지장궤양이 2명 그리고 조직 생검상 만성 활동성 위염 을 보이는 경우가 14명이었다. 환자의 위 전정부에서 생 검된 조직은 면역조직화학적 염색을 실시하였고 염색에 사용된 항체는 anti-MUC5AC, anti-MUC6, anti-MUC1 이었다. 결과 : H. pylori 감염시 MUC5AC가 염색된 분포는 표재성 점액세포에서 88%, 유문선세포에서 42%이었다. 제균치료 1개월 후 표재성 점액세포에서 96%, 유문선세 포에서 65%로 의의 있게 증가된 결과를 보였다(p<0.05). MUC5AC 염색 강도는 제균치료 후 두 개의 세포군에서 모두 증가경향이었다. H. pylori 감염시 MUC1과 MUC6 가 염색된 분포는 제균치료 후 유의한 변화는 없었다. MUC6의 염색강도가 표재성 점액세포에서 제균치료 후 유의하게 증가하였다(p<0.05).

위선암에서 MUC2 및 MUC5AC 발현의 임상적 의의

박승배(Sung Bae Park),김대중(Dae Joong Kim),김용석(Yong Seok Kim),김범규(Beom Gyu Kim),지경천(Kyung Choun Chi),임현묵(Hyun Muck Lim),노재형(Jae Hyung Noh),손태성(Tae Sung Sohn),김성(Sung Kim) 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.74 No.3

Purpose: We examined the clinical significance of MUC2 and MUC5AC gene expression in gastric adeno-carcinoma tissues. Methods: Two hundred specimens were obtained from gastric carcinoma patients who underwent gastric cancer operations at Samsung Medical Center between January 2001 and January 2005. MUC2 and MUC5AC expression were examined immunohistochemically, and correlated with clinicopathologic features and prognostic significance. Results: MUC2 expression was positive in 88 tissues (44.0%) and MUC5AC expression was positive in 125 tissues (62.5%). MUC2 expression was associated with cancer advancement, lymph node metastasis, T classification, distant metastasis, and endolymphatic invasion. Loss of MUC5AC expression was significantly related to cancer advancement, lymph node metastasis, advanced T stage, and distant metastasis. MUC2 expression was usually negative in early gastric cancer (78%), but usually positive in advanced gastric cancer (66%). MUC5AC was usually positive in early gastric cancer (74%). The prognosis of the MUC2(-) group was significantly better than the MUC2(+) group (P<0.001). There was no relationship with MUC5AC expression and survival. Multivariate analysis showed that T classification, lymph node metastasis, distant metastasis, endolymphatic invasion, and MUC2 expression were independent prognostic factors, but MUC5AC expression was not. Conclusion: MUC2 and MUC5AC expression correlated with several clinicopathologic parameters (cancer advancement, lymph node metastasis, advanced T classification, distant metastasis). MUC2 expression was a significant independent prognostic factor and positive MUC2 expression suggested poor prognosis. MUC2 expression may have prognostic significance in gastric adeno-carcinomas.

호흡기 상피세포에서 Roflumilast에 의한 MUC5AC와 MUC5B 발현 억제

김준곤,최윤석,박창휘,이영하,김귀옥,송시연,배창훈,김용대 대한이비인후과학회 2014 대한이비인후과학회지 두경부외과학 Vol.57 No.12

Background and Objectives Roflumilast, a selective inhibitor of phosphodiesterase type 4, has an anti-inflammatory property. It has been used in the treatment of chronic inflammatory airway diseases such as chronic obstructive pulmonary disease and asthma. However, the effect of roflumilast on mucus secretion in inflammatory airway epithelial cells has not been reported. Therefore, this study was aimed at investigating the effects of roflumilast on the inflammatory mediator-induced MUC5AC and MUC5B expression in human airway epithelial cells. Materials and Method In human mucin-producing NCI-H292 airway epithelial cells and primary cultures of nasal epithelial cells, the effects of roflumilast on lipopolysaccharide (LPS)- and phorbl-12-myrsitate-13-acetate (PMA)-induced MUC5AC and MUC5B expression were analyzed by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Results Roflumilast attenuated LPS-induced MUC5AC and MUC5B mRNA and glycoprotein expression in NCI-H292 cells. And roflumilast attenuated PMA-induced MUC5AC and MUC5B mRNA and glycoprotein expression in NCI-H292 cells. In addition, roflumilast attenuated LPS and PMA-induced MUC5AC and MUC5B mRNA expression in the primary cultures of nasal epithelial cells. Conclusion These results suggest that roflumilast attenuates MUC5AC and MUC5B expressions in airway epithelial cells. Roflumilast may be a potentially ideal therapeutic agent for the control of mucus-hypersecretion in treating chronic inflammatory airway diseases. Korean J Otorhinolaryngol-Head Neck Surg 2014;57(12):830-5

호흡기 상피세포에서 MUC5AC와 MUC5B 발현에 대한 다중벽 탄소나노튜브의 효과

안지훈,김형근,서보현,최윤석,송시연,배창훈,김용대 대한이비인후과학회 2015 대한이비인후과학회지 두경부외과학 Vol.58 No.8

Background and Objectives Multi-walled carbon nanotubes (MWCNT) are one of the most commonly used nanomaterials to date. Recent studies have demonstrated that MWCNT increase immune response and allergic inflammation in airway epithelial cells. However, the effects of MWCNT on mucin in human airway epithelial cells have not been reported. Therefore, in the present study, the effect of MWCNT on MUC16, MUC5AC, and MUC5B expressions were investigated in human airway epithelial cells. Subjects and Method In mucin-producing human NCI-H292 airway epithelial cells and primary cultures of normal nasal epithelial cells, the effects of MWCNT on MUC16, MUC5AC, and MUC5B expression were analyzed by reverse transcription polymerase chain reaction, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Results In human NCI-H292 airway epithelial cells, MWCNT significantly induced the expression MUC5AC and MUC5B mRNA and the production of MUC5AC and MUC5B protein. However, MWCNT did not induce the expression of MUC16 mRNA. In the primary cultures of normal nasal epithelial cells, MWCNT also induced the expression of MUC5AC and MUC5B mRNA and the production of MUC5AC and MUC5B proteins. Conclusion The results of this study demonstrate that MWCNT induces MUC5AC and MUC5B expression in human airway epithelial cells. These findings provide important information about the biological role of MWCNT on mucus-secretion in human airway epithelial cells.

호흡기 상피세포에서 MUC5AC와 MUC5B 발현에 대한 Betulinic Acid의 효과

김훈성 ( Hoon Sung Kim ),최윤석 ( Yoon Seok Choi ),이준혁 ( Jun Hyeok Lee ),박나경 ( Na Kyung Park ),박창휘 ( Chang Hwi Park ),이영하 ( Young Ha Lee ),김귀옥 ( Gui Ok Kim ),송시연 ( Si Young Song ),배창훈 ( Chang Hoon Bae ),이승호 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0

Background and Objectives MUC5AC and MUC5B are representative secretory mucin genes in the human airway. MUC5AC and MUC5B expression are increased by a variety of inflammatory mediators. Betulinic acid, a naturally occurring pentacyclic triterpenoid, is known to have an anti-inflammatory property. However, the effects of betulinic acid on mucin secretion of airway epithelial cells still have not been reported. Therefore, in this study, the effect of betulinic acid on inflammatory mediators-induced MUC5AC and MUC5B expression was investigated in human airway epithelial cells. Materials and Method In the mucin-producing human NCI-H292 airway epithelial cells, the effects of betulinic acid on interleukin-1β (IL-1β)-, lipopolysaccharide (LPS)-, and phorbol myristate acetate (PMA)-induced MUC5AC and MUC5B expression were analyzed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results Betulinic acid attenuated IL-1β-, LPS- and PMA-induced MUC5B mRNA and glycoprotein expression in NCI-H292 cells. Betulinic acid did not attenuate IL-1β-, LPS- and PMA-induced MUC5AC mRNA and glycoprotein expression in NCI-H292 cells. Conclusion These results suggest that betulinic acid attenuates IL-1β-, LPS- and PMA-induced MUC5B expression in airway epithelial cells. Therefore, betulinic acid may modulate a control of mucus-hypersecretion in airway inflammatory disease. Korean J Otorhinolaryngol-Head Neck Surg 2014;57(8):526-32

호흡기 상피세포에서 MUC5AC와 MUC5B 발현에 대한 Betulinic Acid의 효과

김훈성,최윤석,이준혁,박나경,박창휘,이영하,김귀옥,송시연,배창훈,이승호,김용운,김용대 대한이비인후과학회 2014 대한이비인후과학회지 두경부외과학 Vol.57 No.8

Background and Objectives MUC5AC and MUC5B are representative secretory mucin genes in the human airway, whose expressions are increased by a variety of inflammatory mediators. Betulinic acid, a naturally occurring pentacyclic triterpenoid, is known to have an anti-inflammatory property. However, the effects of betulinic acid on mucin secretion of airway epithelial cells still have not been reported. Therefore, in this study, the effect of betulinic acid on inflammatory mediators-induced MUC5AC and MUC5B expressions was investigated in human airway epithelial cells. Materials and Method In the mucin-producing human NCI-H292 airway epithelial cells, the effects of betulinic acid on interleukin-1β (IL-1β)-, lipopolysaccharide (LPS)-, and phorbol myristate acetate (PMA)-induced MUC5AC and MUC5B expressions were analyzed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Results Betulinic acid attenuated IL-1β-, LPS-, and PMA-induced MUC5B mRNA and glycoprotein expression in NCI-H292 cells. On the other hand, betulinic acid did not attenuate IL-1β-, and LPS-, but induced PMA-induced MUC5AC mRNA and glycoprotein expressions in NCI-H292 cells. Conclusion These results suggest that betulinic acid attenuates IL-1β-, LPS-, and PMA-induced MUC5B expression in the airway epithelial cells. Therefore, betulinic acid may modulate a control of mucus-hypersecretion in airway inflammatory diseases. Korean J Otorhinolaryngol-Head Neck Surg 2014;57(8):526-32